The development of novel immunosuppressive drugs has caused a dramatic increase in the short term survival of organ transplants in recent years. The use of such drugs, however, is associated with side effects such as opportunistic infections, tumors and ultimately, chronic rejection.
The recent description of two subsets of T helper cells (Th), with different cytokine secretion profiles and activities, may provide a new paradigm for immunoregulation of organ allograft rejection (Mosmann et al., Inmunol. Today, 8:223, 1987). The two Th cell subsets, designated Th1 and Th2, can be characterized on the basis of their respective cytokine production profiles. Th1 cells produce and secrete interferon-gamma (IFN-.gamma.), lymphotoxin (LT) and interleukin-2 (IL-2). On the other hand, Th2 cells produce and secrete interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6) and interleukin-10 (IL-10).
Acute organ allograft rejection may result from responses associated with the pro-inflammatory cytokines IL-2, IFN-.gamma., and TNF-.alpha., derived from Th1 cells. Down-regulation of Th1 activity, therefore, may be a useful immunomodulatory therapy. It is also well known that infection by certain parasitic organisms can modulate the balance between Th1 and Th2 activity. By way of example, Sher and coworkers have demonstrated that a depression of Th1-type responses can be achieved by helminth infection (Sher et al., J. Immunol., 147:2713, 1991). Helminth infection can also result in up-regulation or stimulation of Th activity. Nematode induced up-regulation can encompass stimulation of IgE (and IgG1 in mice or IgG4 in humans), mast cell hyperplasia and eosinophilia in all species, including humans.
It is well known that the immune modulation associated with helminth infection is unrelated to the worm antigens per se. For example, greater than 80 percent of the IgE generated during Nipostrongylus brasiliensis (N. brasiliensis) infection was found not to be directed to N. brasiliensis (Jarrett et al., Clin. Exp. Immunol., 24:326, 1976).
Such induced up-regulation may be due to the cross-regulatory actions of the Th1/Th2 system. The Th1 and Th2 subsets have been found to be cross-regulatory with respect to differentiation and activity. By way of example, cytokines produced by Th2 cells (e.g., IL-4 and IL-10) inhibit Th1 cell growth and cytokine production and ablate the effects of Th1 cytokines (e.g., IFN-.gamma.) on their targets, while IFN-.gamma. inhibits Th2 function (Powrie et al., Immunol. Today, 14:270, 1993).
The concept of resistance or susceptibility being related to Th1/Th2 balance has also been suggested in a variety of other models, including AIDS, and even successful pregnancy. The finding of pro-inflammatory cytokines IL-2, IFN-.gamma., TNF-.alpha. and IL-6 in rejecting kidney allografts lends support to the hypothesis that Th1-type T cells orchestrate the immune response, which culminates in rejection. It likely that a Th1/Th2 balance is established within the graft which changes over time, differs among individuals, and is dependent on the treatment administered but that the cellular mechanisms behind graft rejection, such as infiltration by macrophages and CTL, are consistent with the activities of Th1 cells.